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Obesity and the metabolic syndrome (MetS) predispose to multiple diseases and to accelerated cell aging as indexed by accelerated shortening of telomeres in peripheral blood mononuclear cells (PBMC's). Major depressive disorder (MDD) is often associated with MetS and is also associated with increased disease risk and PBMC telomere shortening. A potential role of leptin in telomere shortening has been suggested, but prior results have been inconsistent and no study has yet assessed this relationship in MDD. The goal of this study was to assess the relationship between serum leptin concentrations and PBMC telomere length in MDD and in controls and to assess whether this relationship is mediated by body-mass index (BMI) or the homeostatic model assessment of insulin resistance (HOMA-IR), two principal components of the MetS.Eighteen medication-free MDD subjects (11 female, 7 male, mean age 37.1 + 2.7 years) and 17 healthy controls (11 female, 6 male, mean age 37.8 + 3.0 years) had blood drawn for assay of fasting morning levels of leptin, glucose, and insulin and PBMC telomere length. The groups did not differ on BMI (24.66 + 3.72 vs. 24.77 + 4.29, respectively, n.s.). Analyses were co-varied for age and sex, with and without BMI.In the combined group, serum leptin concentrations were inversely correlated with telomere length (r= − 0.33, p0.30, and t=1.49, p>0.10, respectively), but leptin concentrations remained significantly correlated with telomere length (t= − 2.88, p=0.007).Relatively high leptin concentrations, in the presence or absence of increased BMI and insulin resistance, may be a risk factor for telomere shortening. While this was demonstrated here in individuals with MDD, a similar relationship in non-depressed individuals cannot be ruled out because of the small sample size.

Increasing awareness of treatment resistance and the emergence of tolerance on once effective medications have facilitated acceptance of a variety of novel drug combination treatment strategies. Although clinical practice is based for the most part on a literature that is still seriously lackin in well-controlled and methodologically rigorous studies, the risk-benefit ratio in most cases seems acceptable if a clear understanding of the possible therapeutic and adverse interactions on the part of both the physician and the patient prevails. Historically, drug combinations have emerged out of serendipity, but increasingly, theories of complimentary drug action serve a heuristic propose in guiding clinical research efforts, and in testin the purposed mechanisms of actions for each of the drugs separately.

Ketoconazole, an antiglucocorticoid drug, was administered to 10 hypercortisolemic depressed patients for up to 6 weeks. Three patients dropped out because of side effects or intercurrent illness. The remaining seven had significant ketoconazole-associated decreases in serum cortisol levels and in depression ratings. Antiglucocorticoid agents may be useful probes for investigating the sequelae of hypercortisolemia in patients with major depression.

Much has been said about the psychological implications of the various stages of life as regards suicide. The life span is generally depicted as involving a dynamic, ever-changing interplay of both internal and external forces that largely determine the nature and stability of a person’s emotional experience. A major focus has been on developmental tasks and goals that, if incompletely or tardily accomplished, become an obstacle to subsequent growth, and a source of psychic pain conducive to self-destructive activity.

In three independent studies with different designs and groups of subjects, the authors found that 1) depressed patients who did not suppress cortisol when given dexamethasone (compared to suppressors and normal control subjects), 2) healthy volunteers given a single 1-mg dose of dexamethasone (compared to those given placebo), and 3) healthy volunteers given 80 mg/day of prednisone for 5 days (compared to those given placebo) all made significantly more errors of commission in verbal memory tasks, with no significant change in their rates of errors of omission. These findings raise the possibility of specific corticosteroid-related cognitive impairments.

Smoking is a significant public health problem, and existing treatments have demonstrated only moderate efficacy in assisting smokers to quit. Varenicline, recently approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products as an aid to smoking cessation treatment, has a novel mechanism of action, targeting the specific nicotinic acetylcholine receptor (nAChR) associated with nicotine-induced behaviors (alpha4beta2 nAChR). It has both agonistic and antagonistic properties that together are believed to account for reduction of craving and withdrawal as well as blocking the rewarding effects of smoking. The clinical efficacy and tolerability of varenicline has been demonstrated in phase III clinical trials involving more than 2,000 cigarette smokers. At the end of the treatment period in two 12-week, multicenter, randomized, double-blind, placebo-controlled studies, patients receiving varenicline (1 mg twice daily) experienced an increase in the odds of quitting smoking by nearly fourfold compared with those receiving placebo, and almost twofold compared with the odds for patients receiving 150 mg bupropion SR (sustained release) twice daily. In these two trials where patients were randomized to either varenicline or bupropion, the efficacy of varenicline was consistently superior at 12 weeks; this result sustained significance at 24 weeks in both studies and up to 52 weeks in one study. Nausea, a common adverse event reported in clinical trials, led to few treatment discontinuations. Its targeted mechanism of action, superior efficacy and excellent tolerability make varenicline a welcome and useful addition to the therapeutic options for smoking cessation.

Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

The association between depressive disorders and subsequent cognitive decline is controversial. We tested the hypothesis that elderly women (aged 65 years and older) without dementia but with depressive symptoms have worse cognitive function and greater cognitive decline than women with few or no symptoms.As part of an ongoing prospective study, we evaluated 5781 elderly, mostly white, community-dwelling women. Women completed the Geriatric Depression Scale short form. Three cognitive tests--Trails B, Digit Symbol, and a modified Mini-Mental State Examination--were administered at baseline and approximately 4 years later. Baseline, follow-up, and change scores for the cognitive tests were analyzed by analysis of covariance and Kruskal-Wallis analysis; the odds of cognitive deterioration (or =3-point decline on the modified Mini-Mental State Examination) were determined by logistic regression.At baseline, 211 (3.6%) of the women had 6 or more depressive symptoms. Only 16 (7.6%) of these women were receiving antidepressant medication. Increasing symptoms of depression were associated with worse performance at baseline and follow-up on all 3 tests of cognitive function (P.001 for all comparisons). For example, the baseline Digit Symbol score (mean +/- SD) was 45.5 +/- 10.7 among women with 0 to 2 symptoms of depression, 40.3 +/- 10.7 for women with 3 to 5 symptoms, and 39.0 +/- 11.3 for women with 6 or more symptoms. After adjusting for the baseline score, cognitive change scores were also inversely associated with the number of depressive symptoms (P.001 for all comparisons). Odds ratios for cognitive deterioration using 0 to 2 symptoms as the reference were 1.6 (95% confidence interval, 1.3-2.1) for 3 to 5 symptoms and 2.3 (95% confidence interval, 1.6-3.3) for 6 or more symptoms. Results were similar after being adjusted for education, age, health status, exercise, alcohol use, functional status, and clinic site.Depressive symptoms in older women are associated with both poor cognitive function and subsequent cognitive decline. Mechanisms underlying the association between these 2 common conditions need further exploration.

identified. The average dose was 300 mg/d. This study supports the f'mdings in the adult population of the anti-aggressive effect of clozapine. In this sample, there was a high comorbidity of psychosis with other disorders such as Tourette's Disorder, Obsessive-Compulsive Disorder and Posttraumatic Stress Disorder. The sample as a whole, had numerous pharmacological failures. Blood cell counts remained stable. In four patients, when clozapine was discontinued, symptomatology reemerged including the aggression, in only one patient, clozapine was discontinued because of side effects that were not hematological in nature. The most common side effects were salivation and weight gain. This study supports previous findings of the anti-aggressive effects of clozapine. Clozapine's affinity for the 5-HT 2 receptors might explain this effect.

In both the abstract and "Comment" section of their recent report, Higley et al 1 state that plasma cortisol concentrations and "stress hormones" (plural emphasized) were positively correlated with a measurement of aggression. It is not clear what this is based on, since the correlation between plasma cortisol and aggression ratings in Table 2 of their article is essentially zero. If this is not a typographical error, it puts into question the authors' claim of a relationship between increased stress, serotonin, and aggression in their animal population, as does the absence of significant intercorrelations between 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) and the other stress measures identified, ie, CSF norepinephrine and plasma corticotropin. Although it is in support of other work, the conclusion that the findings indicate that excessive aggression is related to diminished CSF 5-HIAA concentrations in nonhuman primates also seems overstated, in view of the

Many patients with major depression show deficits in information processing to a degree that parallels the severity of the mood disorder. Parallel findings of alteration in hormonal systems known to modulate memory functions suggest that the biological and cognitive changes described may be functionally linked. A specific goal for norepinephrine and the limbic hypothalamic-pituitary-adrenal axis is hypothesized and related to specific components of the alteration in information processing. The cognitive and mood effects of stimulant compounds in normal and depressed patient populations and parallels between the biologic and cognitive changes seen in normal aging and those observed in depression are considered.

The authors present a pattern of electrophysiologic abnormalities from a computer-analyzed, electroencephalogram (EEG) and averaged evoked potential (AEP) test battery used in the assessment of a group of patients with eating disorders. This finding may be correlated with non-suppression on the dexamethasone suppression test (DST). The authors also review the relevant EEG literature, and discuss the potential role of this test battery in the evaluation of this patient population.

Evidence exists to suggest that there are neurochemical responses common to the development of tolerance to and dependence on a variety of psychoactive drugs. Experimental data indicates that pituitary peptides such as corticotropin and vasopressin, in addition to the endorphins, influence the development of physical dependence on either morphine or ethanol. If these findings are supported by further investigations with human subjects, various manipulations of pituitary-adrenal function, such as the administration of corticotropin and vasopressin analogs or drugs such as dexamethasone, may prove to be of clinical utility.

Male and female Sprague-Dawley rats were tested for turning preferences in a multiple alley maze. The left and right caudate-putamen were dissected and assayed for norepinephrine and dopamine. Dopamine was not found to be lateralized contralateral to turning preference for females as a group. However, dopamine was significantly lateralized contralateral to the females turning preference if a strong turning bias was present. No relationship between dopamine asymmetry and turning preference was evident for males. Females were found to have norepinephrine significantly lateralized to the left caudate-putamen; in males greater striatal norepinephrine levels were equally distributed between left and right sides. This sexual dimorphism in norepinephrine lateralization was not related to turning preference.

The authors present some of the criticisms that have been leveled against the federal peer review system of approving or disapproving monetary grants. They then summarize the process used by the National Institute of Mental Health's Psychiatry Education Branch to judge grant applications, focusing on the disposition of 527 applications reviewed in November 1974-January 1975. They found that the wide distribution of the reviewers by geography, subspecialty, experience, sex, and ethnicity, plus the steps taken to guard against bias and ensure fairness, were effective, refuting many of the criticisms of the group peer review process.

Neuroleptic dosing practices during inpatient treatment of schizophrenia were examined for 1490 admission episodes during 1973 through to 1982 in two wards of a university hospital. Chlorpromazine-equivalent dose levels (CPZE) declined 50% between 1974 and 1980. As expected, length of treatment and choice of drug were both strongly related to CPZE. The general drop in CPZE is not explained by shorter treatment and changing choice of drug, however. Oral fluphenazine, haloperidol, and depot fluphenazine are used to higher maximum levels than chlorpromazine and other neuroleptics, when maximum dose is reached after one week or longer. The results illustrate that by seeking an appropriate statistical model, aggregate trends in dosing practices can be described while avoiding several of the shortcomings of earlier surveys of hospital practice.

The relationship between hypothalamic-pituitary-adrenal (HPA) dysregulation and skin conductance measures of habituation, stimulus specificity, and dishabituation was investigated in psychiatric patients exhibiting depressed affect. As a group, depressed patients showed a relative failure to dishabituate when compared with control subjects. Nonsuppression of cortisol following dexamethasone was associated with decreased response specificity as reflected in direct response measures and baseline skin conductance level. The impairment of response specificity to a novel stimulus is consistent with previous studies demonstrating a role for cortisol in the regulation of selective attention processes.

Researchers have found that state-dependent learning is associated with the administration of a wide variety of drugs. Recent data suggest that similar phenomena may occur secondary to endogenous changes in neuroregulatory substances. The authors point out that awareness of such changes in cognitive processing strategies and abilities should help to further our understanding of the phenomenology of psychiatric states and should generate psychotherapeutic techniques designed to maximize the transfer of information across psychiatric states.

There is considerable diversity of opinion as to the nature of the response of depressed patients to amphetamine infusion. The authors report on the clinical response of 18 endogenously depressed patients to double-blind, intravenous administration of amphetamine or saline. Although the drug produced activation, mood elevation, and recall of emotionally charged material in the group as a whole, there was considerable heterogeneity of response as well as a tendency for response dimensions to vary independently of one another. The heterogeneity of clinical response may be associated with differences in underlying clinical, biological, and genetic variables in affectively ill patients.

Patients with major endocrine disorders frequently experience significant changes in mood and mentation. Similarly, many individuals presenting as psychiatric patients have pathologic alterations in neuroendocrine function. Although pathognomic behavioral changes are rare, increased recognition of characteristic symptom complexes may lead to earlier diagnosis and improved treatment planning.

The effect of long-term lithium carbonate treatment on parameters of immediate, short-, and long-term memory was examined in a group of bipolar affectively ill patients. The lithium treatment group recalled significantly fewer words across trials on a verbal learning task than a group of bipolar affectively ill patients receiving no medication. The ability to consistently recall material for which prior learning had been demonstrated was also decreased and accounted for most of the variance in total number of words recalled. Possible mechanisms of effect are discussed.

Noradrenergic mechanisms have been postulated to account for the anticonvulsant and psychotropic effects of carbamazepine. In order to assess this possibility in man, cerebrospinal fluid (CSF) was obtained from affectively ill patients before and during treatment with carbamazepine (average duration 29 days) at doses averaging 860 mg/day, achieving blood levels of 8.86 micrograms/ml. Neither plasma nor CSF norepinephrine (NE) nor CSF 3-methoxy-4-hydroxy-phenylglycol (MHPG) was significantly altered by carbamazepine. Baseline medication-free values in 21 depressed patients were not predictive of the degree of subsequent clinical antidepressant response. CSF NE decreased in four manic patients treated with carbamazepine. The many effects of carbamazepine on noradrenergic mechanisms in animals are discussed in relationship to these first studies of carbamazepine in man.

Disturbances in thyroid regulation occur much more commonly in the female population and are not infrequently associated with behavioral symptomatology. Recognition of such gender differences in associational risk is important, for it may alter the clinical algorithm of assessment techniques and treatment interventions. From a scientific standpoint, interpretation of existing data and design of future studies exploring the relationship between thyroid regulation and behavior is likely to be improved if such sex differences are more commonly recognized and addressed.